Morphin

Biological Agents -> Plant Toxins

Pharmaceutical

DEA NFLIS-Drug Category -> Narcotic Analgesics

DEA Schedule II Controlled Substance

Pharmaceuticals -> Illicit drugs

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Metabolite of Codeine

Pharmaceuticals -> Listed in ZINC15

log Kow = 0.89

0.8

Prisms

White, crystalline alkaloid

Small rhombic prisms or needles from dilute alcohol as the monohydrate

In water, 1.49X10+2 mg/L at 20 °C

Insoluble in water

One gram dissolves in about 5000 mL water, 1100 mL boiling water

One gram dissolves in about ... 210 mL alcohol, 98 mL boiling alcohol, 1220 mL chloroform, 6250 mL ether, 114 mL amyl alcohol, 10 mL boiling methanol, 525 mL ethyl acetate

For more Solubility (Complete) data for MORPHINE (6 total), please visit the HSDB record page.

Breast Feeding; Lactation; Milk, Human; Analgesics, Opioid; Narcotics

Pharmaceuticals

Opioid analgesics

Warning

H302 (98.6%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P263, P264, P270, P271, P272, P280, P301+P317, P302+P352, P304+P340, P318, P319, P321, P330, P333+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 72 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

DEA schedule II controlled substance

Regulation (EC) No 178/2002 (amended)

Status: Active Update: 20-03-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/19364

Morphine: Does not have an individual approval but may be used under an appropriate group standard

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any of the following opium derivatives, its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. /Benzylmorphine; Desomorphine; Dihydromorphine; Methyldihydromorphine; Morphine methylbromide; Morphine methylsulfonate; Morphine-N-oxide; Nicomorphine; Normorphine/[Table#3870]

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Morphine (DEA Code Number: 9300) is included on this list.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Ethylmorphine (DEA Code Number: 9190) is included on this list. /Ethylmorphine/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Narcotic drugs. Unless specifically excepted or unless listed in another schedule: (1) Any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below: Not more than 50 milligrams of morphine per 100 milliliters or per 100 grams, with one or more active, nonnarcotic ingredients in recognized therapeutic amounts. DEA Code Number: 9810.

For more FDA Requirements (Complete) data for MORPHINE (7 total), please visit the HSDB record page.

DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability (1984) DHHS Pub No. (ADM)87-1332.[Available from, as of August 11, 2008: http://www.nida.nih.gov/pdf/Monographs/MonographIndex.html]

DHHS/NIDA; Research Monograph Series 54: Mechanisms of Tolerance and Dependence (1984) DHHS Pub No. (ADM)88-1330.[Available from, as of August 11, 2008: http://www.nida.nih.gov/pdf/Monographs/MonographIndex.html]

DHHS/NIDA; Research Monograph Series 59: Current Research on the Consequences of Maternal Drug Abuse (1985) DHHS Pub No. (ADM)85-1400.[Available from, as of August 11, 2008: http://www.nida.nih.gov/pdf/Monographs/MonographIndex.html]

DHHS/NIDA; Research Monograph Series 60: Prenatal Drug Exposure: Kinetics and Dynamics (1985) DHHS Pub No. (ADM)85-1413.[Available from, as of August 11, 2008: http://www.nida.nih.gov/pdf/Monographs/MonographIndex.html]

For more Special Reports (Complete) data for MORPHINE (9 total), please visit the HSDB record page.

Morphine salts are sensitive to changes in pH and morphine is liable to be precipitated out of solution in an alkaline environment. Compounds incompatible with morphine salts include aminophylline and sodium salts of barbiturates and phenytoin.

Morphine sulfate has been reported to be physically or chemically incompatible with solutions containing aminophylline, amobarbital sodium, chlorothiazide sodium, phenytoin sodium, heparin sodium, meperidine hydrochloride, methicillin sodium (no longer commercially available in the US), nitrofurantoin sodium, pentobarbital sodium, phenobarbital sodium, sodium bicarbonate, sodium iodide, and thiopental sodium (no longer commercially available in the US).

Morphine sulfate injection should be protected from light and stored at 15-30 °C; the injection should not be frozen. ... Morphine sulfate extended-release liposomal injection (DepoDur) should be stored under refrigeration at 2-8 °C but may be stored at 15-30 °C for up to 7 days in sealed, unopened vials. ... Morphine sulfate soluble tablets, extended-release capsules and tablets, and oral solution should be stored in tight, light-resistant containers at 15-30 °C; freezing of the oral solution should be avoided.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Morphine was qualitatively detected in the breast milk of a woman receiving postpartum intrathecal morphine treatment(1). In an in vitro experiment, morphine was shown to diffuse across the placental barrier(2).

Morphine diffuses across the placenta and traces also appear in milk ...

The universally accepted 300 ng/mL cut-off limit for opiate assays stated to be mandatory for all drug screening laboratories by the Substance Abuse and Mental Health Services Administration, has been questioned recently due to positive results being obtained following the ingestion of poppy seed containing food products. To establish the plausibility of the 'the poppy seed defence' the concentrations of codeine, norcodeine, morphine, normorphine and thebaine (a potential marker for seed ingestion) in several varieties of poppy seeds from different countries were quantified by GC-MS. The country of origin of the seed specimen analyzed and the preparation of the seeds prior to their culinary use was found to influence the alkaloid concentration determined. The maximum morphine and codeine concentrations determined in the seeds were found to be 33.2 and 13.7 micrograms/g seed respectively. In addition, thebaine concentrations were found to vary with each seed sample analyzed. Following the consumption of bread rolls (mean 0.76 g seed covering per roll) by four subjects, all urine specimens analyzed produced negative results (using the Dade Bebring EMIT II opiate screening assay) with the exception of one subject (body weight 63.0 kg) who consumed two poppy seed rolls. In this subject opiate positive screening results were obtained for up to 6 h post ingestion with maximum urinary morphine and codeine concentrations of 832.0 ng/mL (at 2-4 hr post ingestion) and 47.9 ng/mL (at 0-2 hr post ingestion) respectively being achieved. Following the ingestion of poppy seed cake containing an average of 4.69 g of seed per slice by four individuals, opiate positive screening results were obtained for up to 24 hr. In one subject (dose equivalent to 0.07 g poppy seed/kg body weight) maximum urinary morphine and codeine concentrations of 302.1 ng/mL (at 0-2 hr) and 83.8 ng/mL (at 2-4 hr) respectively were recorded. The elimination of thebaine was found to vary widely between individuals, therefore suggesting that its absence from a specimen is not necessarily indicative of opiate abuse. These findings demonstrate that the poppy seed defence could be used as an argument in medico-legal and employment medical cases. Great care should therefore be taken when interpreting the data produced when screening for opiates. Meadway C et al; Forensic Sci Int 96(1): 29-38 (1998) 9800363 BODY Heroin, morphine, and codeine are among the most abused opiate analgesics today. Analysis of individuals' urines for morphine and codeine is used as an indication of prior ingestion of these drugs. Poppy seeds and products containing poppy seeds are found to have small amounts of morphine and codeine (usually less than 200 ug morphine/g seeds and much less codeine), which is enough to produce a positive urine test for opiates. This manuscript reviews current data on the analysis of various poppy seed products and urine specimens from individuals ingesting these products. A brief review of the metabolism and elimination of these drugs is presented, with general guidelines for differentiation of poppy seed use versus condone, morphine, or heroin abuse.

A report /on/ the analysis of poppy seed filling for morphine and codeine content /is presented/. Concentrations in the range 17.4 to 18.6 micrograms/g (morphine) and 2.3 to 2.5 micrograms/g (codeine) were found in different lots of the filling, which is widely used in baking. The effect of consumption of poppy seed filling on opiate urinalysis results is discussed. Morphine concentrations as high as 4.5 g/L are reported, with persistence of concentrations greater than 0.3 mg/L as long as 35 hr after consumption.

In the treatment of morphine overdosage, primary attention should be given to the re- establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The pure opioid antagonists, such as naloxone, are specific antidotes against respiratory depression which results from opioid overdose. Naloxone should be administered intravenously; however, because its duration of action is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. If the response to naloxone is suboptimal or not sustained, additional naloxone may be administered, as needed, or given by continuous infusion to maintain alertness and respiratory function; however, there is no information available about the cumulative dose of naloxone that may be safely administered. (L1712)

Deaths due to ingesting rachacha, which is a homemade paste obtained by decocting poppy heads, are very rare. No fatalities have been recorded in scientific publications. This product is not considered to be very dangerous by its users. We are reporting the first deaths (a 30-year-old man and a 28-year-old woman), after ingesting rachacha balls and alcohol consumption during an evening with a friend. Signs compatible with acute anoxia were observed during autopsy. Toxicological analyses highlighted the presence of morphine and codeine in the blood, urine and bile, with an absence of 6-acetylmorphine. Concomitant consumption of alcohol certainly played a role in the occurrence of death. The black paste found at the scene was identified as rachacha. The mean of consumption (orally) was confirmed by the presence of morphine and codeine in the gastric contents of both victims. The analysis of hair samples was performed to reveal the substance consumption history. Therefore, a possibility of contamination by sweat and/or putrefactive liquids in the post-mortem period must be considered for the interpretation of the results. These two cases show that taking rachacha can be dangerous, especially when combined with the consumption of substances which could potentiate respiratory depression induced by morphine.

Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. /The aim of the study was/ to investigate analgesic effects of morphine when co-administered with adjuvant drugs. Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans.

Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50% effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.

Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune-dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signaling participant), NF-kappaB, Interleukin-1beta (IL-1beta; as a downstream proinflammatory effector molecule) and the mu opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5 g/kg) and alcohol (2.5 g/kg) interaction with morphine (5 mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. Wild-type male Balb/c mice and matched genetically-deficient TLR2, TLR4, and MyD88 strains were utilized, together with pharmacological manipulation of MOR, NF-kappaB, TLR4 and Interleukin-1beta. Alcohol induced significant LORR in wild-type mice; this was halved by MyD88 and TLR4 deficiency, and surprisingly nearly completely eliminated by TLR2 deficiency. In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-kappaB-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1beta. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-kappaB-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction.

For more Interactions (Complete) data for MORPHINE (25 total), please visit the HSDB record page.

Therapy with morphine has not been linked to serum enzyme elevations. Hepatitis B and C are common among persons with opiate addiction and illicit injection drug use, but the opiates themselves appear to have little hepatotoxic potential. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to morphine. Morphine has little hepatic metabolism and is generally excreted unchanged in the urine, perhaps accounting for their relative lack of hepatotoxicity.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1000(SRC), determined from a structure estimation method(2), indicates that morphine is expected to have low mobility in soil(SRC). The pKa of morphine is 8.21(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the neutral species of morphine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Morphine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1000(SRC), determined from a structure estimation method(2), indicates that morphine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.3X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). A pKa of 8.21(5) indicates morphine will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow of 8.95(7) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), morphine, which has an estimated vapor pressure of 1.8X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase morphine may be removed from the air by wet or dry deposition(SRC). Morphine exhibits a UV maximum of 285 nm in acid and 298 nm in alkali(3) suggesting that it may be susceptible to direct photolysis by sunlight(SRC).

The morphine content of 83 poppy seed samples ranged from less than 1 mg/kg to 270 mg/kg; baking mixes containing poppy seed were found to contain morphine concentrations ranging from less than 0.3 mg/kg to 4 mg/kg(1).

The universally accepted 300 ng/mL cut-off limit for opiate assays stated to be mandatory for all drug screening laboratories by the Substance Abuse and Mental Health Services Administration, has been questioned recently due to positive results being obtained following the ingestion of poppy seed containing food products. To establish the plausibility of the 'the poppy seed defense' the concentrations of codeine, norcodeine, morphine, normorphine and thebaine (a potential marker for seed ingestion) in several varieties of poppy seeds from different countries were quantified by GC-MS. The country of origin of the seed specimen analyzed and the preparation of the seeds prior to their culinary use was found to influence the alkaloid concentration determined. The maximum morphine and codeine concentrations determined in the seeds were found to be 33.2 and 13.7 micrograms/g seed, respectively. In addition, thebaine concentrations were found to vary with each seed sample analyzed. Following the consumption of bread rolls (mean 0.76 g seed covering per roll) by four subjects, all urine specimens analyzed produced negative results (using the Dade Bebring EMIT II opiate screening assay) with the exception of one subject (body weight 63.0 kg) who consumed two poppy seed rolls. In this subject opiate positive screening results were obtained for up to 6 h post ingestion with maximum urinary morphine and codeine concentrations of 832.0 ng/mL (at 2-4 hr post ingestion) and 47.9 ng/mL (at 0-2 hr post ingestion) respectively being achieved. Following the ingestion of poppy seed cake containing an average of 4.69 g of seed per slice by four individuals, opiate positive screening results were obtained for up to 24 hr. In one subject (dose equivalent to 0.07 g poppy seed/kg body weight) maximum urinary morphine and codeine concentrations of 302.1 ng/mL (at 0-2 hr) and 83.8 ng/mL (at 2-4 hr), respectively, were recorded. The elimination of thebaine was found to vary widely between individuals, therefore suggesting that its absence from a specimen is not necessarily indicative of opiate abuse. These findings demonstrate that the poppy seed defense could be used as an argument in medico-legal and employment medical cases. Great care should therefore be taken when interpreting the data produced when screening for opiates.

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

Among the more common adverse effects of morphine administration is constipation. This effect occurs via stimulation of μ-opioid receptors on the myenteric plexus, inhibiting gastric emptying and reducing peristalsis. Other common side effects include central nervous system depression, nausea, vomiting, and urinary retention. Respiratory depression is among the more serious adverse reactions of opiate use that is especially important to monitor in the postoperative patient population. Other reported side effects include lightheadedness, sedation, and dizziness. Patients often report nausea and vomiting, which is why morphine is frequently administered with an antiemetic such as ondansetron. Other effects include euphoria, dysphoria, agitation, dry mouth, anorexia, and biliary tract spasms, which is why some physicians will avoid morphine when patients present with right upper quadrant pain and suspect possible biliary tract pathology. Morphine can also affect the cardiovascular system and reportedly can cause flushing, bradycardia, hypotension, and syncope. Patients can experience pruritis, urticaria, edema, and other skin rashes. One meta-analysis indicated that intrathecal morphine significantly increases postoperative nausea and vomiting, urinary retention, and pruritus. Adrenal insufficiency has been reported with prolonged opioid use, typically after more than one month. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. Diagnosis should be confirmed with testing, and treatment involves physiologic corticosteroid replacement.

EXPERIMENTAL: Morphine was qualitatively detected in the breast milk of a woman receiving postpartum intrathecal morphine treatment(1).

Morphine diffuses across the placenta and traces also appear in milk ...

/The authors/ report the case of an infant who was breastfed while his mother was receiving low doses of morphine. Morphine concentration in his serum was in the analgesic range (4 ng/mL), while concentrations in the milk varied substantially in three samples collected within 2 hours (10, 100, 12 ng/mL). The calculated dose that the infant must have received to achieve the observed serum concentration had to be between 0.8 to 12% of maternal dose, based on reference literature values of clearance and bioavailability. The current perception that maternal morphine exposure is safe for the breastfed infant is based on ... 50 year old data which were determined by an analytical method 1000 fold less sensitive than the present HPLC, thus leading to a likely erroneous conclusion.

IDENTIFICATION AND USE: Morphine is white and crystalline solid. It is an opiate agonist used, often in the form of its sulfate salt, to relieve severe, acute pain or moderate to severe, chronic pain. The drug is also used parenterally as a supplement for analgesia during labor. Morphine is the drug of choice in relieving pain of myocardial infarction. It may be used in veterinary care as an analgesic (narcotic), preanesthetic, antitussive, and antiperstaltic. HUMAN EXPOSURE AND TOXICITY: Morphine sulfate misuse is essentially observed among regular heroin injectors. The most serious adverse effect of morphine is respiratory depression. Constipation is a common side effect. In patients with myocardial infarction, morphine causes a decrease in systemic vascular resistance which may result in a transient fall in systemic arterial pressure leading to severe hypotension. Morphine should be used with caution in patients with toxic psychoses. Several manufacturers recommended that morphine sulfate should not be used in patients with known or suspected paralytic ileus. All opioid analgesics are metabolized by the liver and should be used with caution in patients with hepatic disease because increased bioavailability after oral administration of cumulative effects may occur. Morphine has the potential to precipitate or exacerbate asthmatic attacks and should be avoided in patients with a history of asthma. An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness. Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. ANIMAL STUDIES: The clinical signs associated with morphine intoxication in animals differ from those in man. While humans usually die in coma, animals die during or after a series of convulsion. Intoxicated dogs show signs of vomition, delirium, clonic spasms and stertorous breathing. In the cat, a hypnotic effect is rarely seen, the action being that of motor excitement. Reversible lens opacities developed in mice, rats, and guinea pigs in less than an hour after administration of morphine, which has been explained by a reduction in blinking, a resultant exposure of the cornea, increased evaporation, and dehydration of the anterior segment of the eye, causing temporary loss of transparency. A study with rats pointed out the risk of hepatic damage due to long term usage of morphine via disturbance of oxidant-antioxidant balance. Morphine might increase testicular cell apoptosis and reduce sperm concentration by upregulating the expressions of Bax and Caspase-3 in the rat model of morphine tolerance. In the newborn rat, morphine causes profound respiratory depression. In a mouse study, opioid receptors were spatiotemporally expressed in the uterus during the peri-implantation period. It was further observed, that although systemic morphine treatment exerts no apparent adverse influence on preimplantation ovarian secretion of progesterone and estrogen, the aberrant activation of opioid signaling by morphine induces impaired luminal epithelial differentiation, decreased stromal cell proliferation, and poor angiogenesis, and thus hampers uterine receptivity and embryo implantation. In a rat study, swimming exercise was found to be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. In another rat study, results suggested that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. ECOTOXICITY STUDIES: Opioids are considered as emerging contaminants in aquatic ecosystems. Mussels were exposed to morphine for 14 days. Morphine reduced the lysosome membrane stability of bivalves, and induced significant changes in the activity of antioxidant enzymes as well as lipid peroxidation levels. Slight increase in primary DNA fragmentation was noticed, while no fixed genetic damage and alterations of the filtering rate were found.

Signs and Symptoms of Overdose

The precise mechanism of the analgesic action of morphine is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects. Morphine first acts on the mu-opioid receptors. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. It has been shown that morphine binds to and inhibits GABA inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory signals, pain modulation can proceed downstream.

/AQUATIC SPECIES/ Opioids are considered as emerging contaminants in aquatic ecosystems, mainly due to their large illicit consume worldwide. Morphine (MOR) is the main opiate and it was commonly found at measurable concentrations in freshwaters. Even though its occurrence is well documented, limited information is available regarding its hazard to nontarget organisms. The aim of this study was the evaluation of sublethal effects induced by MOR to the freshwater bivalve Dreissena polymorpha. ...Mussels /were exposed/ to two MOR concentrations (0.05 ug/L and 0.5 ug/L) for 14 days and ...the sublethal effects /were investigated/ by a suite of biomarkers. The Neutral Red Retention Assay (NRRA) was used as a test of cytotoxicity, while the oxidative stress was evaluated by the activity of antioxidant and detoxifying enzymes, namely catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), and by measuring the levels of lipid peroxidation (LPO) and protein carbonylation (PCC). The genetic damage was assessed by the Single Cell Gel Electrophoresis (SCGE) assay, the DNA diffusion assay and the micronucleus test (MN test). Finally, the filtration rate of D. polymorpha was evaluated in order to investigate possible physiological effects. Both tested concentrations reduced the lysosome membrane stability of bivalves, but only the highest MOR concentration induced significant changes in the activity of antioxidant enzymes (SOD, CAT, and GPx) and increase in lipid peroxidation levels. Slight increase in primary DNA fragmentation was noticed, while no fixed genetic damage and alterations of the filtering rate were found.

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any of the following opium derivatives, its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. /Benzylmorphine; Desomorphine; Dihydromorphine; Methyldihydromorphine; Morphine methylbromide; Morphine methylsulfonate; Morphine-N-oxide; Nicomorphine; Normorphine/[Table#3870]

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Morphine (DEA Code Number: 9300) is included on this list.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Ethylmorphine (DEA Code Number: 9190) is included on this list. /Ethylmorphine/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Narcotic drugs. Unless specifically excepted or unless listed in another schedule: (1) Any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below: Not more than 50 milligrams of morphine per 100 milliliters or per 100 grams, with one or more active, nonnarcotic ingredients in recognized therapeutic amounts. DEA Code Number: 9810.

For more FDA Requirements (Complete) data for MORPHINE (7 total), please visit the HSDB record page.

N02AA01

N02AA01

N - Nervous system

QN - Nervous system

N02AA01

Morphine binding to opioid receptors blocks transmission of nociceptive signals, signals pain-modulating neurons in the spinal cord, and inhibits primary afferent nociceptors to the dorsal horn sensory projection cells. Morphine has a time to onset of 6-30 minutes. Excess consumption of morphine and other opioids can lead to changes in synaptic neuroplasticity, including changes in neuron density, changes at postsynaptic sites, and changes at dendritic terminals. Intravenous morphine's analgesic effect is sex dependent. The EC₅₀ in men is 76ng/mL and in women is 22ng/mL. Morphine-6-glucuronide is 22 times less potent than morphine in eliciting pupil constriction.

Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. The mu-opioid receptor is integral to morphine's effects on the ventral tegmental area of the brain. Morphine's activation of the reward pathway is mediated by agonism of the delta-opioid receptor in the nucleus accumbens, while modification of the respiratory system and addiction disorder are mediated by agonism of the mu-opioid receptor.

Visual analysis of the direct electroencephalograph has revealed that morphine /slowed/ the predominant frequency and /increased/ high-voltage delta activity.

Morphine has a half life of 2-3 hours.

... The mean terminal half-life of morphine following epidural injection is 90 minutes (range: 39-349 minutes), which is similar to the half-life of the drug reported after IV or IM administration (1.5-4.5 hours).

CSF concentrations of morphine decline in a biphasic manner following epidural injection of conventional morphine sulfate injection, with an early distribution half-life of 1.5 hours and a terminal half-life of about 6 hours.

Following epidural administration of a 10-, 15-, or 20-mg dose of morphine sulfate extended-release liposomal injection, the half-life reportedly is 16.2, 20, or 23.9 hours, respectively.

Following intrathecal administration of /morphine/, the mean reported CSF half-life is 90 minutes (range: 42-136 minutes).

For more Biological Half-Life (Complete) data for MORPHINE (6 total), please visit the HSDB record page.

Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate.

... patients on therapeutic codeine also test positively for morphine, because morphine is a codeine metabolite.

/Heroin/ is converted metabolically by ester hydrolysis first to 6-monoacetylmorphine (heroin-specific metabolite) and then to morphine by hydrolysis for the second acetate ester. When the heroin base enters the body, it is fairly lipophilic, so a portion of the dose readily crosses the blood-brain barrier into the central nervous system where the hydrolysis of the two esters can take place. Morphine is less lipophilic than heroin and does not cross back across the blood-brain barrier as readily. Morphine readily undergoes the additional phase I metabolic transformation of oxidative N-demethylation by CYP2D6. Phase II (conjugation) reactions of morphine include formation of the glucuronide conjugates at the hydroxyl moieties at positions 3 and 6. The glucuronides are then excreted. Note that the aromatic ring stays intact throughout the metabolic transformations, illustrating the stability imparted by aromaticity.

Morphine is metabolized principally in the liver and undergoes conjugation with glucuronic acid principally at the 3-hydroxyl group. Secondary conjugation also occurs at the 6-hydroxyl group to form the 6-glucuronide, which is pharmacologically active, and to a limited extent the 3,6-diglucuronide. Plasma concentrations of the 3-glucuronide, which is inactive, and the 6-glucuronide substantially exceed those of unchanged drug, and the latter metabolite appears to contribute substantially to the drug's pharmacologic activity. Elimination of the drug may be reduced substantially in neonates compared with older children and adults. Morphine is excreted in urine mainly as morphine-3-glucuronide. In addition to the 3,6-diglucuronide, other minor metabolites that have been described includes normorphine and the 3-ethereal sulfate. ... In patients with renal impairment, accumulation of morphine-6-glucuronide occurs, which can result in enhanced and prolonged opiate activity.

The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The two major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Small amounts of morphine-3,6-diglucuronide also may be formed.

For more Metabolism/Metabolites (Complete) data for MORPHINE (12 total), please visit the HSDB record page.

76I7G6D29C

MORPHINE

Mechanisms of Action [MoA] - Full Opioid Agonists

Established Pharmacologic Class [EPC] - Opioid Agonist

Morphine is an Opioid Agonist. The mechanism of action of morphine is as a Full Opioid Agonist.

MORPHINE

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.

Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.

Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a Tmax of 15 minutes and oral morphine has a Tmax of 90 minutes, with a Cmax of 283nmol/L. The AUC of morphine is 225-290nmol\*h/L.

70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces.

The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg.

The apparent clearance of intravenous or subcutaneous morphine is 1600 mL/min.

Morphine crosses the placenta at term. ... Pregnant patients in labor clear the parent compound almost twice as fast. Infants younger than 1 month of age have prolonged half-life of morphine compared to older children. The clearance of morphine approaches adult values in the second month of life. The milk to plasma ratio of morphine is 2.5:1. Although significant infant plasma levels may develop, breast-feeding can usually be performed safely. A breast-feeding infant may absorb 0.8% to 12% of the maternal dose.

Morphine sulfate is variably absorbed from the GI tract. Food may increase the extent of GI absorption of morphine sulfate administered as conventional preparations. Food may decrease the rate of absorption of morphine sulfate administered as extended-release capsules; however, the extent of absorption of the drug does not appear to be affected.

Analgesics, Opioid; Narcotics

Morphine (DEA Code Number: 9300) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Analgesic (in form of acetate, hydrochloride, tartrate, and other soluble salts).

MEDICATION

Use (kg) in Switzerland (2009): >250

codeine; 7,7',8,8'-tetrahydro-4,5alpha:4',5'alpha-diepoxy-17,17'-dimethyl-2,2'-bimorphinanyl-3,3',6alpha,6'alpha-tetrol (pseudomorphine); 6,7,8,14-tetrahydro-4,5alpha-epoxy-6-methoxy-17-methylmorphinan-3-ol (oripavine); 7,8-didehydro-4,5alpha-epoxy-17-methylmorphinan-3,6alpha,10beta-triol (10R-hydroxymorphine); 7,8-didehydro-4,5alpha-epoxy-17-methyl-6-oxomorphinan-3-ol (morphinone) /morphine hydrochloride; morphine sulfate/

(1972) 5.3X10+5 G

(1973) 6.75X10+5 G

Depending on its source, the morphine content of poppy straw or dried exudate may be as high as about 20%. ... Usually, the crude opium is extracted with water and filtered, and the aqueous extract concentrated, mixed with ethanol, and made strongly basic with ammonium hydroxide. Morphine usually precipitates, while the other bases remain in solution, and is further purified by crystallization as its sulfate.

Morphine is obtained by extraction of poppy capsules or opium (opium contains 9-14% morphine, depending on the source) with water, precipitation with aqueous Na2CO3-solution, washing of the precipitate with ethanol and dissolving in diluted acetic acid.

Morphine is usually administered as the sulfate, although the hydrochloride and the tartrate are used in similar doses. Doses are expressed as the salts. Dosage routes include the oral, subcutaneous, intramuscular, intravenous, intraspinal, and rectal routes.

Available commercially as the free base monohydrate, acetate trihydrate, tartrate, tetrahydrate, various phosphate and other derivatives.

Derivatives: codeine; hydromorphine; normorphine

Oral: Avinza, Kadian, Oramorph, MS Contin; Parenteral: Astramorph/PF, Duramorph, Infumorph; Rectal: RMS. /Morphine sulfate, from table/

Common street names: Dreamer, Emsel, First Line, God's Drug, Hows, M.S., Mister Blue, Morf, Morpho, and Unkie.

Pharmaceuticals

Pharmaceuticals -> Nervous System -> Analgesics -> Opioids -> Natural opium alkaloids -> Narcotics

Because the synthesis of morphine is difficult, the drug is still obtained from opium or extracted from poppy straw.

Principal alkaloid of opium.